Aging depletes the primary trophic hormones, growth hormone (GH), insulin-like growth factor type I (IGF-I) and testosterone (Te). Inferred sequelae include diminished anabolic drive to muscle, bone, brain and sexual organs, and accentuated visceral adiposity, insulin resistance, dyslipidemia and cardiovascular risk. A major unmet need is to understand the fundamental mechanisms that enforce GH/IGF-I deprivation in older individuals with aging-related relative Te deficiency. Compelling data obtained during the initial tenure of the MERIT award frame the thesis that aging and Te-derived estradiol (E2) availability governs an ensemble of interlinked peptides that direct GH secretion. The minimal ensemble comprises GH-releasing hormone (GHRH), somatostatin (SS), GH-releasing peptide (ghrelin, GHRP), and GH and IGF-I. From this vantage, we pose the following mechanistic hypotheses: Hypothesis I. In older men, repletion of E2 will stimulate pulsatile GH secretion by 3 mechanisms: (i)/(ii) enhancing feedforward drive of GH secretion by endogenous GHRH and endogenous ghrelin, and (iii) attenuating inhibition of GH secretion by endogenous somatostatin (SS). Hypothesis II. In older men, supplemental E2 will potentiate the putative capabilities of ghrelin to: (i) amplify GH secretion driven by pulsatile GHRH stimulation; and (ii) augment rebound-like GH secretion evoked by intermittent SS inhibition. Because no single peptide signal controls GH output, unique analytical tools and experimental strategies will be applied to aid interpretation. The expectation is to clarify how E2 deficiency in older individuals, including those receiving androgen-withdrawal therapies for urological neoplasms, exacerbates aging-associated GH and IGF-I depletion. The outcomes should provide a fundamental rational basis for constructing novel interventions to forestall frailty-related disability, morbidity and mortality in older men. PUBLIC HEALTH RELEVANCE: Estrogen in men, as in women, determines bone strength. We test here the new idea that estrogen also is the major regulator of growth hormone secretion in aging men.